Synthesis of substituted p-stereogenic vinylphosphine oxides by olefin cross-metathesis

[reaction: see text] Substituted vinylphosphine oxides have been prepared in good yield and exclusive (E)-olefin selectivity via olefin cross-metathesis using Grubbs and Hoveyda-type ruthenium catalysts. In addition, metathesis of chiral vinylphosphine oxides proceeds without racemization of the phosphorus chirality center, providing easy access to functionalized chiral nonracemic (E)-alkenylphosphine oxides.     

Synthesis of erythromycin derivatives via the olefin cross-metathesis reaction

Olefin cross metathesis (CM) was applied to the synthesis of 6-O-substituted erythromycin derivatives. The reactions were catalyzed by transition metal alkylidene complexes, particularly bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubbs' first-generation catalyst). This approach allowed for the elaboration of the 6-O-allyl group of highly functionalized macrolides at various stages of the synthetic sequence, affording 6-O-3-aryl-propenyl products with excellent E-selectivity. Little or no self-dimerization of the reacting components was found in the crude mixtures. Preliminary kinetic data accounts for the observed cross-selectivity based on substrate reactivity and steric factors.     

Chemoselective construction of substituted conjugated dienes using an olefin cross-metathesis protocol

[Reaction: see text] Various substituted conjugated dienes have been made by olefin cross-metathesis. Using either electronic or steric "protection," one of the olefins of the conjugated diene was deactivated relative to the other for cross-metathesis. The reactions proceed with very high chemoselectivity and, when steric deactivation is used, very high diastereoselectivity.     

An olefin cross-metathesis approach to vinylphosphonate-linked nucleic acids

[reaction: see text]. The synthesis of vinylphosphonate-linked nucleotide dimers has been achieved using an olefin cross-metathesis (CM) reaction as a key step. The 1,3-dimesityl-4,5-dihydroimidazol-2-ylidine-containing catalyst 5 (Grubbs' second-generation catalyst) was found to be the superior catalyst for this transformation. Both metathesis partners were readily available using known methodology, and the vinylphosphonate-linked dimer was produced with high levels of (E)-selectivity (>20:1) in 58% yield (70% based on recovered starting material).     

Synthesis of trisubstituted alkenes via olefin cross-metathesis

[formula: see text] Trisubstituted alkenes have been prepared for the first time via intermolecular olefin cross-metathesis, using 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ruthenium alkylidene complexes 3a,b in good yields with moderate E selectivity. In addition, protected alcohols near the geminal disubstituted olefin improve reactivity for cross-metathesis.     

Synthesis of vinyl-functionalized oxazoles by olefin cross-metathesis

A ruthenium-based catalyzed olefin cross-methathesis reaction involving 2- and 4-vinyl-functionalized oxazoles was developed. A wide range of olefinic partners was coupled in good to excellent yields and high stereoselectivities under mild conditions. This methodology offers new opportunities for the synthesis of a plethora of biologically active natural products.     

Understanding the effect of allylic methyls in olefin cross-metathesis

A series of NMR spectroscopy experiments have been conducted with both the model compound, 3-methyl-1-pentene and the corresponding ADMET monomer 3,6,9-trimethylundeca-1,10-diene (11) to better understand the effect of allylic methyls during olefin metathesis chemistry. Traditional ADMET catalysts such as Schrock’s molybdenum (1), and Grubbs’ ruthenium 1st and 2nd generation (2 and 3) were examined under cross-metathesis and ADMET conditions. Regardless of catalyst selection, 50% or less metathesis conversion was observed for all reactions, especially in the case of the more sterically encumbered diene. With Schrock’s molybdenum catalyst 1, the reaction leads to an accumulation of the non-productive metallacyclobutane, trapping the catalyst in an inactive form. With Grubbs’ ruthenium catalysts 2 and 3, the substrate coordinates to the metal center primarily to yield non-productive metathesis, which results in a build-up of the methylidene complex leading to catalyst decomposition. These results are directly correlated to the orientation of the substrate’s bulk during the metallacyclobutane formation, the alkyl branch being adjacent to the metal center in the case of the molybdenum catalyst 1, and opposite to it in the case of ruthenium catalyst 2 and 3.     

Use of olefin cross-metathesis to release azide-containing sugars from solid support

[reaction: see text] The octenediol linker used during automated oligosaccharide assembly is cleaved by olefin cross-metathesis. Until now, this linker could not be applied to sugars containing azides. A detailed study of the cleavage reaction served as basis for the development of a new protocol using the [(H(2)Imes)(3-Br-py)(2)(Cl)(2)Ru=CHPh] catalyst and 1-pentene. Efficient release of azide-protected carbohydrates from solid support can be readily achieved.     

Heteroaromatic synthesis via olefin cross-metathesis: entry to polysubstituted pyridines

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.     

Synthesis of chlorophyll a glycoconjugates using olefin cross-metathesis

Chlorophyll a glycoconjugates were obtained by cross-metathesis between olefin moieties of chlorophyll derivatives and allylβ-galactopyranoside tetraacetate.     

Synthesis of the pro-gly dipeptide alkene isostere using olefin cross-metathesis

An approach to the synthesis of dipeptide olefin isosteres using intermolecular olefin cross-metathesis is presented. In particular, a synthesis of the Pro-Gly isostere (1) is reported. Conversion of N-BOC-proline into the corresponding vinyl-substituted carbamate provides the N-terminal cross-metathesis partner (2). Methyl 3-butenoate (3) is employed as the C-terminal component. Treatment of the two partners in an optimized molar ratio affords the cross product 1 (83% yield). Three other examples are demonstrated to evaluate the potential of the approach.     

Self-selection in olefin cross-metathesis: the effect of remote functionality

Olefin cross-metathesis (CM) is potentially an attractive method for generating dynamic combinatorial libraries (DCLs). In order for the CM reaction to be useful for DCL production, the course of the reaction and product distribution must be relatively insensitive to functionality remote from the reacting centers. We report on the CM of a series of allyl- and homoallylamides that are strongly dependent on remote functionality. This includes an unusual example of a cis-selective CM. [Reaction: see text]     

Rate enhanced olefin cross-metathesis reactions: the copper iodide effect

Copper iodide has been shown to be an effective cocatalyst for the olefin cross-metathesis reaction. In particular, it has both a catalyst stabilizing effect due to iodide ion, as well as copper(I)-based phosphine-scavenging properties that apply to use of the Grubbs-2 catalyst. A variety of Michael acceptors and olefinic partners can be cross-coupled under mild conditions in refluxing diethyl ether that avoid chlorinated solvents. This effect has also been applied to chemistry in water at room temperature using the new surfactant TPGS-750-M.     

Total synthesis of epicoccamides A and D via olefin cross-metathesis

Epicoccamides A and D were synthesized through a route that utilizes fragment coupling via olefin cross-metathesis as a key step. The right-hand segment of the epicoccamides was synthesized by a tandem O-acylation–migration reaction, and the left-hand segments were stereoselectively synthesized through a modified version of Crich’s β-selective mannosylation. The previously assigned absolute configuration of the epicoccamide D was confirmed, and that of epicoccamide A was assigned as (5S,2′S) based on the NMR and CD spectra. This Letter provides the first example of the total synthesis of epicoccamide A.     

Synthesis of tri-substituted vinyl boronates via ruthenium-catalyzed olefin cross-metathesis

Tri-substituted vinyl pinacol boronates, which are key reactive intermediates in a variety of transformations, are synthesized using ruthenium-catalyzed olefin cross-metathesis of α-substituted vinyl boronates and various alkenes. Cross-metathesis of 2-isopropenyl pinacol boronate proceeds with moderate yield and high Z-selectivity when sterically unhindered cross partners are used. Cross-metathesis of vinyl boronates that possess α-substitution larger than a methyl group is also achieved. Yield and Z-selectivity are lower in these cases, and the success of a cross-metathesis reaction is highly dependent on the steric bulk surrounding the double bond of the α-substituted vinyl boronate.     

Application of olefin cross-metathesis to organometallics. Synthesis of unsaturated ferrocenyl alcohols and ketones

[reaction: see text] The application of olefin cross-metathesis to terminally unsaturated alpha-hydroxy- and alpha-ketoferrocenes is reported. Both substrates provided the terminally functionalized olefins in moderate to good yield. These examples represent the first cases of cross-metathesis of substrates containing an organometallic functional group.     

Assembling the prenylneoflavone system through a Pechmann condensation/Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis sequence

Monatshefte für Chemie - Chemical Monthly - The multistep synthesis of a prenylneoflavone through a sequence of the Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis reaction...     

Synthesis of (E)-3'-phosphonoalkenyl modified nucleoside phosphonates via a highly stereoselective olefin cross-metathesis reaction

The synthesis of (E)-3'-phosphonoalkenyl and 3'-phosphonoalkyl modified nucleoside analogues with a β-D-erythrofuranose moiety is reported. The highly stereoselective olefin cross-metathesis reaction was applied to introduce the phosphonoalkenyl group at the 3'-position of the sugar moiety with absolute (E)-selectivity. The 3',6'-cyclomonophosphonic acids of 3'-phosphonoethyl-β-D-erythrofuranosyl nucleosides were synthesized via a dehydrative intramolecular cyclization reaction. None of the synthesized compounds shows significant in vitro activity against HIV, HCV, and RSV.     

Synthesis of functionalized vinyl boronates via ruthenium-catalyzed olefin cross-metathesis and subsequent conversion to vinyl halides

Functionalized vinyl pinacol boronates suitable for Suzuki cross-coupling reactions are synthesized using ruthenium-catalyzed olefin cross-metathesis of 1-propenyl pinacol boronate and various alkenes, including functionalized and 1,1-disubstituted alkenes. The resultant boronate cross products are stereoselectively transformed into predominantly Z-vinyl bromides and E-vinyl iodides. The vinyl bromides may be synthesized in a two-step, one-pot synthesis from a variety of olefins, resulting in a Z-selective formal vinyl bromide cross-metathesis reaction.     

Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/Heck-cyclisation-elimination sequence

Heck reactions were performed on α,β-unsaturated-δ-sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the β position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.